CD36, also known as platelet glycoprotein IV or IIIb, is an 88 kDa membrane protein expressed on the surface of a wide variety of cell types, including adipocytes, skeletal muscle cells, platelets, endothelial cells, and monocytes/macrophages (Febbraio et al., J. Clin. Invest., 108:785-91 (2001)). Initially identified for its binding to collagen and thrombospondin (TSP-1) in platelets, CD36 is a class B scavenger receptor recognizing a variety of ligands including long-chain fatty acids, modified LDL, anionic phospholipids, Plasmodium falciparum-infected erythrocytes, and apoptotic cells (Febbraio et al., J. Clin. Invest., 108:785-91 (2001); Abumrad et al., J. Biol. Chem., 268:17665-8 (1993); Tandon et al., J. Biol. Chem., 264:7576-83 (1989); Greenwalt et al., Blood, 80:1105-15 (1992)).
Several recent findings suggest a role for CD36 as an important regulator of the metabolic pathways involved in insulin-resistance. CD36 facilitates the membrane transport of long-chain fatty acids (FA) into muscle and adipose tissues (Ibrahimi et al., Proc. Natl. Acad. Sci. USA, 93:2646-51 (1996)). Increased FA availability can induce insulin resistance if the capacity of adipose tissue to store triglycerides and/or that of muscle to oxidize FA is exceeded (Lewis et al., Endocr. Rev., 23:201-29 (2002)). As a result, alterations in CD36 level may be involved in the development of diet-induced insulin-resistance, as suggested by findings in rodents (Hajri et al., J. Clin. Invest., 109:1381-9 (2002)). Homozygous disruption of the CD36 locus in mice leads to hepatic insulin-resistance with high plasma free fatty acids and triglycerides (Febbraio et al., J. Biol. Chem., 274:19055-62 (1999); Goudriaan et al., J. Lipid. Res., 44:2270-7 (2003)). Transgenic rescue of CD36 in the spontaneously hypertensive rat (SHR) strain, in which the CD36 gene is severely mutated, ameliorates the metabolic syndrome typical of this animal model (Aitman et al., Nat. Genet., 21:76-83 (1999); Pravenec et al., Nat. Genet., 27:156-8 (2001)). Furthermore, CD36 is regulated by the peroxisome proliferator activated receptor gamma (PPARγ) and is a gene target of thiazolidinediones (TZDs), agonists of this nuclear receptor (Tontonoz et al., Cell, 93:241-52 (1998)). Up-regulation of adipocyte or muscle CD36 by TZDs appears to mediate some of the insulin sensitizing effects of these drugs (Qi et al., J. Biol. Chem., 277:48501-7 (2002)).